K. D. Buchanan

Responses of atrial natriuretic peptide and brain natriuretic peptide to exercise in patients with chronic heart failure and normal control subjects.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are known to be elevated in patients with chronic heart failure at rest. While it is known that during exercise the circulating level of ANP increases in patients with heart failure, the response of BNP to exercise in these patients relative to control subjects is unclear. Ten patients with stable chronic heart failure and 10 normal control subjects performed symptom‐limited exercise with respired gas analysis. All patients had depressed left ventricular ejection fractions (LVEF). Patients had lower peak oxygen consumption PV˙O2) than the control group [median (range) 1.18 (0.98–1.76) vs. 1.94 (1.53–2.31) L min−1; P < 0.001]. Circulating plasma levels of ANP and BNP were higher at rest in patients than in control subjects [ANP 335 (140–700) vs. 90 (25–500) pg mL−1; BNP 42 (25–50) vs. 20 (10–20) pg mL−1], and at peak exercise [ANP 400 (200–1000) vs. 130 (10–590); BNP 46 (40–51) vs. 20 (10–30)]. The rise in ANP at peak exercise was significant in patients compared with the resting level, but not in control subjects. For BNP, there was a significant rise in patients but no change in control subjects. The circulating plasma levels of both peptides showed a strong negative correlation with LVEF (ANP, P < 0.005; BNP, P < 0.0001) and, to a less extent, with RVEF. It is possible that BNP may give a better indication of cardiac function.

Neuroendocrine changes in chronic cardiac failure

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.

Variable patterns of atrial natriuretic peptide secretion in man

Abstract Peripheral circulating levels of atrial natriuretic peptide may exhibit short‐term variation compatible with a pulsatile pattern of secretion. We obtained samples every 2 min for 90 min from the antecubital vein of 16 patients with chronic cardiac failure and 13 controls. Overall levels were higher in the patients (median and quartiles 230 (125,325) vs. 26 (16,48) ng l‐1; P<0·001). In both groups there was considerable variability, with 10 (2–12) peaks, 9 (7–15) troughs (both defined as >2 SD from the mean) and 16 (13–18) pulses (defined by computer) during the sampling period in controls, and a similar number in patients. We then carried out simultaneous sampling in the pulmonary artery, femoral artery and peripheral vein in eight subjects with normal cardiac function and six patients with impaired function due to valvular heart disease. The pattern of variability was preserved in all three sites in both groups, suggesting intermittent secretion rather than variable breakdown of the peptide in the lung. No changes in right atrial pressure or heart rate were observed to coincide with the variations, but levels of the peptide in the pulmonary artery correlated with right atrial pressure in patients (r = 0·87; P<0·05). The mechanism of such periodicity and its pathophysiological importance remain unknown.

The natriuretic peptide family.

For several decades there has been a search for an endogenous natriuretic-diuretic hormone. As early as 1935, Peters proposed that the ‘fullness’ of the bloodstream may provide a diuretic response on part of the kidney. Experiments by De Wardener et al. [l] provided evidence in support of a hormonal mechanism influencing sodium excretion. If blood from a dog, in which volume expansion with normal saline had been performed, was used to perfuse the kidney of another dog, natriuresis occurred which was independent of the effect of aldosterone or renal perfusion pressure. Other experiments [2] showed that distension of the left atrium with a balloon in an anaesthetized dog led to an increase in urine output, suggesting a specific link between the heart and kidney. The concept that the heart might secrete a hormone which might play a role in the control of sodium and water excretion, and thereby blood volume, was reinforced by the observation of endocrine-like granules in atrial muscle cells [3] and by a change in the degree of granulation with the alteration of sodium and water balance [4]. These experiments led DeBold and co-workers to carry out the key experiments in which they injected rats with extracts prepared from rat atria and ventricles [5]. The natriuretic peptide family currently consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Each peptide exhibits natriuretic-diuretic, vasorelaxant and other functions designed to lower blood pressure and to control electrolyte homeostasis. The natriuretic peptides exert their physiological actions via a series of cellular receptors. Ligand occupancy of the extracellular domain results in the activation of an intracellular guanylate cyclase with an associated rise in cGMP, which is thought to act as the second messenger for the peptides.

Gastrin in health and disease

Edkins in 1905 [ l ] observed that an extract of gastric antral mucosa proved to have extraordinary potency in stimulating gastric acid secretion. However, it was not until approximately 60 years later that the isolation and chemical characterization of gastrin was achieved by Gregory & Tracy in 1964 [2]. The gastrin molecule is composed of a single peptide chain of seventeen aminoacids (G17) having a molecular weight of around 2100. Gastrin exists in two forms, I and 11, the only difference being that I1 has a sulphate molecule attached to the tyrosyl residue in position 12. The synthesis of human gastrin was achieved by Morley in 1968 [3]. Gastrin’s predominant action is on gastric acid secretion and although a variety of other actions have been assigned to it, it is unlikely that any are of great importance. For example, in pernicious anaemia where there is parietal cell failure, although massive circulating gastrin levels are encountered, this hypergastrinaemia does not produce significant abnormalities in the patients. Therefore, gastrin without a functioning parietal cell mass appears to have little role. The hypergastrinaemia in association with achlorhydria is presumably due to a sensitive negative feed-back of acid on gastrin release. The major biological actions of gastrin are manifested by the carboxyl terminal tetrapeptide (Trp-Met-AspPhe-NH2). It is of interest that the related hormone, cholecystolunin-pancreozymin (CCK-PZ), also shares this tetrapeptide and results in some biological overlap between the two hormones. This knowledge has allowed the synthesis of a gastrin pentapeptide (pentagastrin) which is now widely used in tests of parietal cell function. Further advances have been due to the development of a radioimmunoassay for the hormone [4] and to increasing use of chemical techniques particularly gel filtration to identify various gastrin species. Gastrin is predominately located in the antrum of the stomach but small amounts can also be detected in the body and fundus. The duodenum contains significant quantities but thereafter the amount of gastrin diminishes caudally in the gastro-intestinal tract and the ileum and colon contain negligible amounts. There is controversy as to whether gastrin is present in the normal pancreas but it is unlikely that in the human, pancreatic gastrin ever makes a significant contribution. Recently a material immunologically resembling gastrin has been isolated from the human brain but the signficance and function of this material is unknown [5] . It has to be emphasized that the main physiological studies with respect to gastrin have been related to antral gastrin. In common with many other polypeptide hormones such as insulin, glucagon, parathyroid hormone and growth hormone, gastrin exhibits considerable heterogeneity in tissues and in plasma. A gastrin molecule with thirty-four aminoacids has now been identified and is referred to as ‘G34’. This can also exist in the sulphated or non-sulphated form. Even larger molecular species have been identified and have been referred to as ‘big big gastrin’ and in 1974 Gregory & Tracy [6] have isolated a gastrin with thirteen aminoacids which has been termed ‘mini gastrin’, which also exists in the sulphated and non-sulphated forms. G17 is the predominant form in the antrum but the G34 increases in concentration in the duodenum and jejunum. The different gastrins vary in their biological activity and half life in the circulation. In the plasma in the fasting state ‘big big gastrin’ constitutes a major fraction of circulating gastrin whereas G34 is the predominant component identified after eating. This complexity of species is confusing. The different gastrins may represent different hormones or they may represent precursor forms such as is the case of proinsulin and insulin or some of the species may represent degradative forms of the hormone. Indeed some of the species particularly ‘big big gastrin’ may merely be artefacts of the purification and chemical procedures. This variation in molecular species makes difficult the interpretation of radioimmunoassay data. Antisera vary in their affinity for different molecular species and it has been difficult to relate immunoreactivity to biological activity. It is imperative that each radioimmunoassay accurately defines the specificity of the antiserum in use. It is the eventual hope that antisera will be developed to specifically measure different species of gastrin in the tissues and circulation. The most striking clinical condition associated with gastrin pathology is the Zollinger-Ellison syndrome or gastrinorna [ ” I . The tumour most frequently arises in the pancreas and results in massive gastric hypersecretion of acid and severe peptic ulceration. The combination of an elevated plasma gastrin and gastric hypersecretion makes the diagnosis almost certain. Only in a few instances would resort to further tests be required such as the plasma gastrin response to secretin, glucagon or calcium infusion where the gastrinoma patient exhibits a significant elevation of plasma gastrin after these infusions. The accepted surgical approach of removal of the target organ a gastrectomy with removal, if possible, of the tumour -has been challenged by the introduction of the potent H2 receptor antagonist drug, cimetidine. Patients with Zollinger-Ellison syndrome